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Inflammation in Schizophrenia Hinders Brain Cell Growth

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A new study published in the journal Schizophrenia shows important information about how inflammation and neurogenesis interact in people with schizophrenia. The study focuses on the subependymal zone (SEZ), which is an important place for neurogenesis in the brain. The research utilised RNA sequencing to investigate transcriptomic differences between the high inflammation (HI-SCZ) and low inflammation (LI-SCZ) subgroups of schizophrenia patients. The study sheds light on how inflammation might impair neurogenesis, potentially exacerbating the symptoms and progression of schizophrenia.

Schizophrenia is known to be a heterogeneous disorder with varying underlying mechanisms. In recent years, the role of inflammation has come under increasing scrutiny. Approximately 40–50% of schizophrenia cases exhibit elevated inflammation across various brain regions, compared to only around 10% of control subjects​. This study specifically examined the SEZ, also known as the subventricular zone, which is a vital region for generating new neurons from neural stem cells.

The researchers categorised schizophrenia cases into low and high inflammation groups based on the expression of inflammation marker genes. They performed RNA sequencing on SEZ tissue samples from both subgroups to identify differentially expressed genes and pathways associated with inflammation.

The study identified 718 genes that were differentially expressed between the HI-SCZ and LI-SCZ groups. One of the most significant findings was the over-representation of genes in the ‘Hepatic Fibrosis/Hepatic Stellate-Cell Activation’ pathway. This pathway is mostly linked to extracellular matrix (ECM) stability and vascular remodelling. The HI-SCZ group had more angiogenesis and ECM stiffening.

Among the upregulated genes, those related to ECM components, such as various collagen types, were notably increased. Collagen-IV, an important part of the basement membrane, was found to be highly expressed, which suggests changes related to fibrosis that might affect the environment of the neurogenic niche. These changes in the ECM may lead to a stiffer and potentially more fibrotic state, which could impair the niche’s ability to support neurogenesis​​.

The study also highlighted an increase in angiogenesis-related genes in the HI-SCZ subgroup. Angiogenesis, the formation of new blood vessels, is a process closely linked with inflammation and immune cell infiltration. Upregulation of genes like VEGFA (Vascular Endothelial Growth Factor A) and its receptors (FLT1 and FLT4) showed that there was more angiogenesis in the SEZ of people with HI-SCZ. This vascular proliferation could facilitate the entry of immune cells, such as macrophages, into the brain tissue, further exacerbating inflammation​​.

The presence of collagen-IV positive fractone bulbs within the SEZ was another significant finding. These structures, located in the hypocellular gap adjacent to neural stem cells, may play a role in maintaining the neurogenic niche by regulating stem cell activity. The study suggests that alterations in these fractone bulbs due to increased collagen deposition could disrupt normal neurogenic processes​​.

The study’s results show that inflammation in schizophrenia is linked to big changes in the SEZ’s microenvironment, mainly in terms of the ECM’s make-up and the growth of new blood vessels. These changes are likely to impact various stages of neurogenesis, from the maintenance of neural stem cells to the differentiation and migration of new neurons.

One of the notable consequences of increased ECM stiffness is the potential reduction in neuronal differentiation. The study found negative correlations between ECM-related gene expression and markers for neuroblasts and immature neurons. This suggests that a stiffer ECM could inhibit the formation of new neurons, which is crucial for maintaining cognitive functions and brain plasticity​​.

Furthermore, the increased angiogenesis observed in HI-SCZ cases could influence neurogenesis indirectly. Newly formed blood vessels release growth factors that regulate nearby neurogenic cells. However, the study also found that markers for angiogenesis negatively correlated with markers for neuroblasts, indicating a complex relationship that warrants further investigation​.

This research contributes to a growing body of evidence that inflammation plays a critical role in the neuropathology of schizophrenia. By identifying specific transcriptomic changes associated with inflammation, the study provides insights into potential mechanisms that could impair neurogenesis in affected individuals. These findings have significant implications for developing more targeted and personalised treatment strategies for schizophrenia.

The researchers emphasise the need for further studies to explore the causal relationships between inflammation, ECM changes, and neurogenesis. Understanding these interactions could pave the way for novel therapeutic approaches aimed at modulating inflammation and supporting neurogenesis in schizophrenia patients​.

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